To clarify the relationship between the percentage of lung receiving low radiation doses with concurrent chemotherapy and the occurrence of postoperative pulmonary complications in the treatment of esophageal carcinoma. From 117 patients who underwent preoperative chemoradiation for esophageal cancer at our institution between 1998 and 2002, we selected 61 patients for whom complete pulmonary dose–volume histogram (DVH) data were available and analyzed the incidence of pneumonia and acute respiratory distress syndrome (ARDS) in this group. All patients received concurrent chemoradiation therapy, and 39 patients also received induction chemotherapy before concurrent chemoradiation. The median age was 62 years, and the median radiotherapy dose was 45 Gy. The percentage of lung volume receiving at least 10 Gy (V10), 15 Gy (V15), and 20 Gy (V20) were recorded from each pulmonary DVH.

Results: Eleven (18%) of the 61 patients had pulmonary complications, 2 of whom died after progression of pneumonia. Pulmonary complications were noted more often (35% vs. 8%, p = 0.014) when the pulmonary V10 was >40% vs. <40% and when the V15 was >30% vs. < 30% (33% vs. 10%, p = 0.036). An apparent increase in pulmonary complication rate when V20 was >20% vs. <20% (32% vs. 10%, p = 0.079) was not significant. None of the other factors analyzed (surgical procedure, tumor location, use of induction chemotherapy, use of concurrent taxane-based chemoradiation, or smoking history) was associated with the occurrence of pulmonary complications. The median hospital stay was 17 days for patients who had pulmonary complications vs. 12 days for patients who did not (p = 0.08)

Pulmonary complications related to the treatment of lung cancer have been well described, but those associated with the treatment of esophageal cancer have not. However, as the use of preoperative chemoradiation therapy for esophageal cancer increases, the incidence of postoperative complications may increase as well. In their landmark study of 99 patients treated for non–small-cell lung cancer, Graham and colleagues reported the V20 of the total lung volume to be highly correlated with the development of pneumonitis.. In that study, the actuarial incidence of Grade 2 or higher pneumonitis among all patients was 20% at 24 months after treatment, but among patients whose V20 exceeded 40%, the actuarial incidence was 36%. On the basis of those results, we routinely attempt to keep the total lung V20 to less than 40% in the treatment of all thoracic tumors, including cancer of the esophagus. No patients in our study had V20 exceeding 40%. However, three characteristics of the Graham study make their results difficult to generalize to patients with esophageal cancer undergoing multimodality therapy. First, chemotherapy was used in only 42% of patients, and was administered either concurrently or sequentially; by comparison, all patients in our study were given concurrent chemotherapy. Second, no baseline pulmonary function test results were reported for 64 of the 99 patients who had it done, and thus Graham's analysis may have included a heterogeneous group of patients with various functional pulmonary reserves. In contrast, our patients were required to have had “adequate” pulmonary function, otherwise they would not have had surgery; the median preoperative FVC, FEV1, and DLCO values all exceeded 95% of expected values. Third, the total lung volume in the Graham study depended on tumor bulk and extent of disease, because the PTV was subtracted to calculate the lung DVH. Because the primary tumor in our study was extrapulmonary, the lung DVH was calculated from the entire lung, with no volume subtraction. Although some of these limitations result from inherent characteristics of lung tumors and the patients who are predisposed to them, we elected to analyze patients with esophageal tumors in an attempt to minimize potential confounding factors such as these.

The DVH criteria used for radiation pneumonitis may not be applicable for the end point of postoperative pulmonary complications. Our results indicate that for patients undergoing multimodality therapy, the V10 should be kept less than 40% rather than V20 to less than 40%, as previously assumed. The reduced tolerance of the lung after concurrent chemoradiation can be explained by the “two-hit” hypothesis for the development of ARDS and multiple organ failure in the surgical literature (14–17). This hypothesis describes a bimodal model of dysfunctional inflammatory response in which the first “hit” initially elicits a proinflammatory response followed by immunosuppression, and finally a return to immunologic homeostasis. If a second “hit” occurs, it can result in a synergistic proinflammatory or immunosuppressive phase, placing the patient at risk for a heightened inflammatory response that progresses to ARDS or severe immunosuppression that places the patient at risk for the development of pneumonia. Multimodality treatment may fit this model, with preoperative chemoradiation being the first inciting trauma, and resection the second.

Although our analysis showed that a V10 of 40% was the only variable associated with pulmonary complications in the multivariate analysis, no single point on a DVH curve should be considered more informative than the rest of the DVH curve, because of the associations among V10, V15, and V20. The results shown in Table 4 could be considered a general guideline for comparing several treatment plans, bearing in mind the possibility of a volume effect at doses as low as 10–20 Gy.This reduction in pulmonary function even at low doses with concurrent chemotherapy has been reported elsewhere. In a prospective study of 20 patients with esophageal cancer undergoing definitive chemoradiation therapy, Gergel and colleagues reported that the V7–V10 was strongly correlated with decreases in total lung capacity, vital capacity, and DLCO. Similarly, Gopal et al. found that the threshold for DLCO deterioration in 26 patients treated for lung cancer was 13 Gy; 20 of those patients received concurrent chemotherapy

Treating physicians must be aware that the DVH parameters are hardly the only risk factors for postoperative pulmonary complications. A host of biologic factors, including cytokines, may be involved as well. Clinical factors such as performance status, gender, and FEV1 are easily assessable and may be predictors of pneumonitis, as suggested by Robnett and colleagues.. Cytokine levels, serial pulmonary function tests, and functional imaging are worth studying to attempt to predict patients at increased risk for postoperative pulmonary complications. Several models of DVH reduction algorithms are available (24–29); however, potential limitations of some such models are that they are empirically derived, are not readily available for clinical use, and require complicated calculations by the treating physicians. In contrast, simple DVH guidelines such as those shown here are practical and readily available, thereby simplifying the process of comparing plans. However, simplicity comes at a cost in terms of comprehensive information. We did not attempt here to model because our database was limited to V10, V15, and V20, although analyses are currently under way as additional data become available. Currently, there is no clear consensus on the optimal DVH reduction algorithm, and more investigation is needed to best incorporate various treatment response measurements and other clinical variables into a model for accurately predicting complications.

Smoking may alter the risk of developing pneumonitis that is different from developing postoperative pulmonary complications. Hernando and colleagues suggested that smoking at the time of treatment referral for lung cancer may actually be protective against the development of radiation pneumonitis. In contrast, Vaporciyan and colleagues found that patients who smoked within 1 month of pneumonectomy were at a higher risk of developing postoperative pulmonary complications.

We observed clinically significant postoperative pulmonary complications after preoperative chemoradiation for esophageal cancer when more than 40% of the lung received radiation doses as low as 10 Gy. The threshold for lung irradiation for patients to be given multimodality therapy may be lower than previously expected. Radiotherapy techniques that decrease the volume of lung receiving low doses could reduce the risk of postoperative pulmonary complications in the delivery of multimodality therapy.